Cardiovascular disease remains by far the leading cause of death in Western nations and carries an unparalleled health and economic burden. Treatment by balloon angioplasty (percutaneous transluminal angioplasty, or PTA) has been shown to improve life expectancy, but although an alternative to bypass surgery for relieving stenosis of obstructive atherosclerotic blood vessels, the long-term success of the angioplasty is often compromised by the onset of restenosis, thereby requiring reintervention.
In the PTA procedure, an inflatable balloon disposed at the distal end of a catheter is positioned in the region of a stenosis. The balloon is inflated under fluid pressure to reconfigure the narrowed lumen and thereafter permit increased blood flow through the affected artery. It is not unusual that inflation-deflation cycles will be repeated, several times where the narrowing is severe. This mechanical violence to the arterial wall may produce the desired opening of the artery, but in delayed consequence the procedure is followed by an estimated 25%–50% incidence of restenosis, typically within 6 months to 2 years of the procedure (depending on the location), at or near the injured site.
Serial intravascular ultrasound studies have shown that restenosis after stent deployment is due almost entirely to smooth muscle hyperplasia and matrix proliferation. In-stent neointima formation thus remains a major procedural limitation for stent use, limiting both utilization and long-term clinical benefits.
Vessel injury, such as endothelial denudation, injury to the vascular wall, and rupture of the vase vasorum, can result as an unwanted consequence to an angioplasty thereby making the treated site susceptible to restenosis. Upon injury, the ensuing deposition of platelets, in connection with the vessel's healing mechanism, signals smooth muscle cell proliferation within the arterial wall. The deposition of platelets may lead to acute thrombosis in some circumstances. More significantly, the proliferation of smooth muscle cells is a process which frequently continues unabated and has therefore been widely implicated as a prominent factor in the resulting restenosis. No pharmacologic or mechanical intervention has heretofore proven sufficiently effective in preventing restenosis following angioplasties.
Relevant Art. Recent advancements have demonstrated that controlled release platforms can be employed to predictably deliver drugs locally in vivo without additional damage from the materials themselves. These strategies offer the potential to create defined release curves for multiple drugs by combining different materials. Localized drug administration is particularly advantageous where drug retention in the treated locus is required for an effective period of time without appreciably affecting other body tissues.
Reviews of the field of local drug delivery, and the treatment of restenosis may be found in Ettenson and Edelman (200) Vasc Med 5(2):97–102; Gunn and Cumberland (1999) Eur Heart J 20(23):1693–700; and Raman and Edelman (1998) Semin Interv Cardiol 3(3–4):133–7; among others.